Core D: Neuropathology Project Summary Mounting evidence suggests that Alzheimer disease (AD) pathology ? which includes amyloid plaques (made of beta-amyloid peptide), neurofibrillary tangles (made of tau protein), and loss of synapses within the brain ? begins decades before the onset of cognitive symptoms, during a 'preclinical' phase of AD. Data from epidemiological and genetic studies additionally suggest that these pathological changes - and the risk of developing dementia - may be influenced by many factors, including race, sleep, and numerous genetic traits. To meet the goals of the National Alzheimer's Project Act, it will be essential to (1) understand these demographic, behavioral and genetic factors, (2) expand our capacity to detect different aspects and different stages of AD pathology in living individuals, and (3) improve our ability to detect and monitor subtle changes in cognitive function for early diagnosis and the evaluation of treatment effectiveness in clinical trials. In this effort, studies of biofluids and postmortem brain tissue are indispensable. By measuring the levels of beta-amyloid and tau proteins in cerebrospinal fluid (CSF), we can now determine with high accuracy whether living participants have significant AD pathology, even before they show symptoms. This information enables us to enroll cognitively normal participants with or without AD pathology into studies, laying the groundwork to develop new tests, to discover unknown risk factors, and to unravel the mysteries behind known risk factors for AD pathology and subsequent AD dementia. In complementary fashion, comprehensive brain examination can establish not only whether a person had AD, but also other neurodegenerative diseases (e.g., Lewy body disease, frontotemporal lobar degeneration, vascular dementia). Finally, studies of these specimens, themselves, can reveal new secrets about the pathophysiology of AD. The mission of the Heathy Aging and Senile Dementia (HASD) Neuropathology Core (NPC) is to collect, process, analyze, store, and distribute plasma, CSF, and autopsy brain tissue from study participants to support the scientific projects of the HASD Program Project, and other scientific projects around the world. Towards this end, the NPC will measure CSF A?40, A?42, tau, p-tau181, and synaptic/neuronal markers (neurogranin, SNAP-25 and neurofilament light chain), and will also examine brains for neuronal loss, gliosis, vasculopathy, infarcts, white matter pallor, and deposits of A?, hyperphosphorylated tau, alpha-synuclein, and pTDP-43. In support of HASD Projects, these data will: be analyzed for differences between African American and mon- Hispanic white participants (Project 1); evaluate associations of AD pathology and sleep parameters (Project 2); help to identify novel genetic modifiers promoting cognitive reserve and resilience in the presence of AD pathology (Project 3); inform analysis of data from a smartphone application for measuring subtle cognitive decline in preclinical AD (Project 4); and be evaluated for associations with volumetric MRI, amyloid PET, Tau PET, and MRI (Core E).